The prostanoid EP4 receptor is a G protein-coupled receptor that mediates the actions of prostaglandin E2 (PGE2) and is characterized by the longest intracellular C terminus loop when compared to other prostanoid receptors. The EP4 receptor is one of four receptor subtypes of prostaglandin E2 receptors. In general, EP4 receptors couple to G proteins and mediate elevations in cyclic-adenosine monophsophate (“cAMP”) concentration, although they do participate in other pathways as well. Expression of EP4 receptors is controlled by various physiological and pathophysiological processes as these receptors participate in ovulation and fertilization, induce bone formation, T cell factor signaling, protect against inflammatory bowel disease, facilitate Langerhans cell migration and maturation and mediate joint inflammation in a model of collagen-induced arthritis, among others.
U.S. Pat. No. 6,552,067, expressly incorporated herein by reference, teaches the use of prostaglandin EP4 selective agonists for the treatment of methods of treating conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal.
U.S. Pat. No. 6,586,468, expressly incorporated herein by reference, teaches that prostaglandin EP4 agonists may be useful for the prophylaxis and/or treatment of autoimmune disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Sjoegren's syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, post-transplantation graft rejection, asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still's diseases, Kawasaki diseases, burns, systemic granuloma, ulcerative colitis, Crohn's diseases, hypercytokinemia at dialysis and multiple organ failure and shock.
Inflammatory bowel disease constitutes a group of diseases characterized by inflammation of the large and small intestines and manifests symptoms such as diarrhea, pain, and weight loss. Kabashima and colleagues taught that “EP4 works to keep mucosal integrity, to suppress the innate immunity, and to down regulate the proliferation and activation of CD4+ T cells. These findings have not only elucidated the mechanisms of IBD by NSAIDs, but also indicated the therapeutic potential of EP4-selective agonists in prevention and treatment of IBD.” (Kabashima, et. al., The Journal of Clinical Investigation, April 2002, Vol. 9, 883-893).
Various other diseases are mediated by the EP4 receptor such as esophageal ulcers, alcohol gastropathy, duodenal ulcers, non-steroidal anti-inflammatory drug-induced gastroenteropathy and intestinal ischemia. New methods for treating or preventing such diseases are desired.